tbuckley/cabot-search huggingface dataset:
N-of-one differential gene expression without control samples using a deep generative model
Authors: Iñigo Prada-Luengo, Viktoria Schuster, Yuhu Liang, Thilde Terkelsen, Valentina Sora, Anders Krogh
Journal: Genome biology (2023)

Abstract Differential analysis of bulk RNA-seq data often suffers from lack of good controls. Here, we present a generative model that replaces controls, trained solely on healthy tissues. The unsupervised model learns a low-dimensional representation and can identify the closest normal representation for a given disease sample. This enables control-free, single-sample differential expression analysis. In breast cancer, we demonstrate how our approach selects marker genes and outperforms a state-of-the-art method. Furthermore, significant genes identified by the model are enriched in driver genes across cancers. Our results show that the in silico closest normal provides a more favorable comparison than control samples.
Intravascular imaging guided versus coronary angiography guided percutaneous coronary intervention: systematic review and meta-analysis
Authors: Safi U Khan, Siddharth Agarwal, Hassaan B Arshad, Usman Ali Akbar, Mamas A Mamas, Shilpkumar Arora, Usman Baber, Sachin S Goel, Neal S Kleiman, Alpesh R Shah
Journal: BMJ (2023)

Abstract Objective To assess the absolute treatment effects of intravascular imaging guided versus angiography guided percutaneous coronary intervention in patients with coronary artery disease, considering their baseline risk. Design Systematic review and meta-analysis. Data sources PubMed/Medline, Embase, and Cochrane Library databases up to 31 August 2023. Study selection Randomized controlled trials comparing intravascular imaging (intravascular ultrasonography or optical coherence tomography) guided versus coronary angiography guided percutaneous coronary intervention in adults with coronary artery disease. Main outcome measures Random effect meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) were used to assess certainty of evidence. Data included rate ratios and absolute risks per 1000 people for cardiac death, myocardial infarction, stent thrombosis, target vessel revascularization, and target lesion revascularization. Absolute risk differences were estimated using SYNTAX risk categories for baseline risks at five years, assuming constant rate ratios across different cardiovascular risk thresholds. Results In 20 randomized controlled trials (n=11 698), intravascular imaging guided percutaneous coronary intervention was associated with a reduced risk of cardiac death (rate ratio 0.53, 95% confidence interval 0.39 to 0.72), myocardial infarction (0.81, 0.68 to 0.97), stent thrombosis (0.44, 0.27 to 0.72), target vessel revascularization (0.74, 0.61 to 0.89), and target lesion revascularization (0.71, 0.59 to 0.86) but not all cause death (0.81, 0.64 to 1.02). Using SYNTAX risk categories, high certainty evidence showed that from low risk to high risk, intravascular imaging was likely associated with 23 to 64 fewer cardiac deaths, 15 to 19 fewer myocardial infarctions, 9 to 13 fewer stent thrombosis events, 28 to 38 fewer target vessel revascularization events, and 35 to 48 fewer target lesion revascularization events per 1000 people. Conclusions Compared with coronary angiography guided percutaneous coronary intervention, intravascular imaging guided percutaneous coronary intervention was associated with significantly reduced cardiac death and cardiovascular outcomes in patients with coronary artery disease. The estimated absolute effects of intravascular imaging guided percutaneous coronary intervention showed a proportional relation with baseline risk, driven by the severity and complexity of coronary artery disease. Systematic review registration PROSPERO CRD42023433568.
Immunotherapy in Prepatients—Preventing or Promoting a Malignant Transformation?
Authors: Bishal Gyawali, Garth W. Strohbehn
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Cognitive and Emotional Well-Being of Preschool Children Before and During the COVID-19 Pandemic
Authors: Katherine E. Finegold, Julia A. Knight, Rayjean J. Hung, Derrick Ssewanyana, Jody Wong, Kashtin Bertoni, Nadya Adel Khani, Harmoni Watson, Robert D. Levitan, Jennifer M. Jenkins, Stephen G. Matthews, Mark Wade
Journal: JAMA Network Open (2023)

The association between COVID-19 social disruption and young children's development is largely unknown.
Candidate Pathways Underlying Exposure to the COVID-19 Pandemic and Early Child Development—Risk and Resilience
Authors: Morgan R. Firestein, Lauren C. Shuffrey
Journal: JAMA Network Open (2023)

Katherine E. Finegold, EdM; Julia A. Knight, PhD; Rayjean J. Hung, PhD; Derrick Ssewanyana, PhD; Jody Wong, BSc; Kashtin Bertoni, MPH; Nadya Adel Khani, BA; Harmoni Watson, BSc; Robert D. Levitan, MD; Jennifer M. Jenkins, PhD; Stephen G. Matthews, PhD; Mark Wade, PhD, CPsych
Income-based differences in healthcare utilization in relation to mortality in the Swedish population between 2004–2017: A nationwide register study
Authors: Pär Flodin, Peter Allebeck, Ester Gubi, Bo Burström, Emilie E. Agardh
Journal: PLoS Medicine (2023)

Background Despite universal healthcare, socioeconomic differences in healthcare utilization (HCU) persist in modern welfare states. However, little is known of how HCU inequalities has developed over time. The aim of this study is to assess time trends of differences in utilization of primary and specialized care for the lowest (Q1) and highest (Q5) income quantiles and compare these to mortality. Methods and findings Using a repeated cross-sectional register-based study design, data on utilization of (i) primary; (ii) specialized outpatient; and (iii) inpatient care, as well as (iv) cause of death, were linked to family income and sociodemographic control variables (for instance, country of origin and marital status). The study sample comprised all individuals 16 years or older residing in Sweden any year during the study period and ranged from 7.1 million in year 2004 to 8.0 million year 2017. HCU and mortality for all disease as well as for the 5 disease groups causing most deaths were compared for the Q1 and Q5 using logistic regression, adjusting for sex, age, marital status, and birth country. The primary outcome measures were adjusted odds ratios (ORs), and regression coefficients of annual changes in these ORs log-transformed. Additionally, we conducted negative binominal regression to calculate adjusted rate ratios (RRs) comparing Q1 and Q5 with regard to number of disease specific healthcare encounters ≤5 years prior to death. In 2017, for all diseases combined, Q1 utilized marginally more primary and specialized outpatient care than Q5 (OR 1.07, 95% CI [1.07, 1.08]; p &lt; 0.001, and OR 1.04, 95% CI [1.04, 1.05]; p &lt; 0.001, respectively), and considerably more inpatient care (OR 1.44, 95% CI [1.43, 1.45]; p &lt; 0.001). The largest relative inequality was observed for mortality (OR 1.78, 95% CI [1.74, 1.82]; p &lt; 0.001). This pattern was broadly reproduced for each of the 5 disease groups. Time trends in HCU inequality varied by level of care. Each year, Q1 (versus Q5) used more inpatient care and suffered increasing mortality rates. However, utilization of primary and specialized outpatient care increased more among Q5 than in Q1. Finally, group differences in number of healthcare encounters ≤5 years prior to death demonstrated a similar pattern. For each disease group, primary and outpatient care encounters were fewer in Q1 than in Q5, while inpatient encounters were similar or higher in Q1. A main limitation of this study is the absence of data on self-reported need for care, which impedes quantifications of HCU inequalities each year. Conclusions Income-related differences in the utilization of primary and specialized outpatient care were considerably smaller than for mortality, and this discrepancy widened with time. Facilitating motivated use of primary and outpatient care among low-income groups could help mitigate the growing health inequalities.
Chimeric antigen receptors of HBV envelope proteins inhibit hepatitis B surface antigen secretion
Authors: Yang Wang, Qiqi Li, Cheng Li, Cong Wang, Shijie Wang, Wenjie Yuan, Demin Yu, Ke Zhang, Bisheng Shi, Xiaomei Chen, Tiantian Liu, Zhenghong Yuan, Shuping Tong, Michael Nassal, Yu-Mei Wen, Yong-Xiang Wang
Journal: Gut (2023)

Objectives Chronic hepatitis B (CHB) caused by HBV infection greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) plays critical roles in the pathogenesis of CHB. HBsAg loss is the key indicator for cure of CHB, but is rarely achieved by current approved anti-HBV drugs. Therefore, novel anti-HBV strategies are urgently needed to achieve sustained HBsAg loss. Design We developed multiple chimeric antigen receptors (CARs) based on single-chain variable fragments (scFvs, namely MA18/7-scFv and G12-scFv), respectively, targeting HBV large and small envelope proteins. Their impacts on HBsAg secretion and HBV infection, and the underlying mechanisms, were extensively investigated using various cell culture models and HBV mouse models. Results After secretory signal peptide mediated translocation into endoplasmic reticulum (ER) and secretory pathway, MA18/7-scFv and CARs blocked HBV infection and virion secretion. G12-scFv preferentially inhibited virion secretion, while both its CAR formats and crystallisable fragment (Fc)-attached versions blocked HBsAg secretion. G12-scFv and G12-CAR arrested HBV envelope proteins mainly in ER and potently inhibited HBV budding. Furthermore, G12-scFv-Fc and G12-CAR-Fc strongly suppressed serum HBsAg up to 130-fold in HBV mouse models. The inhibitory effect lasted for at least 8 weeks when delivered by an adeno-associated virus vector. Conclusion CARs possess direct antiviral activity, besides the well-known application in T-cell therapy. Fc attached G12-scFv and G12-CARs could provide a novel approach for reducing circulating HBsAg.
Incidence of Recurrence and Time to Recurrence in Stage I to III Colorectal Cancer
Authors: Jesper Nors, Lene Hjerrild Iversen, Rune Erichsen, Kåre Andersson Gotschalck, Claus Lindbjerg Andersen
Journal: JAMA Oncology (2023)

Management of colorectal cancer (CRC) has been updated continuously over the past 2 decades. While the combination of these initiatives has had implications for improved survival, the implications for rates of recurrence remain unexplored.
Analysis across Taiwan Biobank, Biobank Japan, and UK Biobank identifies hundreds of novel loci for 36 quantitative traits
Authors: Chia-Yen Chen, Tzu-Ting Chen, Yen-Chen Anne Feng, Mingrui Yu, Shu-Chin Lin, Ryan J. Longchamps, Shi-Heng Wang, Yi-Hsiang Hsu, Hwai-I. Yang, Po-Hsiu Kuo, Mark J. Daly, Wei J. Chen, Hailiang Huang, Tian Ge, Yen-Feng Lin
Journal: Cell Genomics (2023)

Genome-wide association studies (GWASs) have identified tens of thousands of genetic loci associated with human complex traits. However, the majority of GWASs were conducted in individuals of European ancestries. Failure to capture global genetic diversity has limited genomic discovery and has impeded equitable delivery of genomic knowledge to diverse populations. Here we report findings from 102,900 individuals across 36 human quantitative traits in the Taiwan Biobank (TWB), a major biobank effort that broadens the population diversity of genetic studies in East Asia. We identified 968 novel genetic loci, pinpointed novel causal variants through statistical fine-mapping, compared the genetic architecture across TWB, Biobank Japan, and UK Biobank, and evaluated the utility of cross-phenotype, cross-population polygenic risk scores in disease risk prediction. These results demonstrated the potential to advance discovery through diversifying GWAS populations and provided insights into the common genetic basis of human complex traits in East Asia.
The antitumor activities of anti-CD47 antibodies require Fc-FcγR interactions
Authors: Juan C. Osorio, Patrick Smith, David A. Knorr, Jeffrey V. Ravetch
Journal: Cancer Cell (2023)

While anti-CD47 antibodies hold promise for cancer immunotherapy, early-phase clinical trials have shown limited clinical benefit, suggesting that CD47 blockade alone might be insufficient for effective tumor control. Here, we investigate the contributions of the Fc domain of anti-CD47 antibodies required for optimal in vivo antitumor activity across multiple species-matched models, providing insights into the mechanisms behind the efficacy of this emerging class of therapeutic antibodies. Using a mouse model humanized for CD47, SIRPα, and FcγRs, we demonstrate that local administration of Fc-engineered anti-CD47 antibodies with enhanced binding to activating FcγRs promotes tumor infiltration of macrophages and antigen-specific T cells, while depleting regulatory T cells. These effects result in improved long-term systemic antitumor immunity and minimal on-target off-tumor toxicity. Our results highlight the importance of Fc optimization in the development of effective anti-CD47 therapies and provide an attractive strategy to enhance the activity of this promising immunotherapy.
Prenatal Exposure to Perfluoroalkyl Substances and Child Behavior at Age 12: A PELAGIE Mother–Child Cohort Study
Authors: Hélène Tillaut, Christine Monfort, Florence Rouget, Fabienne Pelé, Fabrice Lainé, Eric Gaudreau, Sylvaine Cordier, Charline Warembourg, Dave Saint-Amour, Cécile Chevrier
Journal: Environmental Health Perspectives (2023)

Per- and polyfluoroalkyl substances (PFAS) are chemical substances spread throughout the environment worldwide. Exposure during pregnancy represents a specific window of vulnerability for child health.Our objective was to assess the impact of prenatal exposure to multiple PFAS on emotional and behavioral functions in 12-y-old children.In the PELAGIE mother-child cohort (France), prenatal exposure to nine PFAS was measured from concentrations in cord serum samples. Behavior was assessed at age 12 y using the parent-reported Strengths and Difficulties Questionnaire (SDQ) and the self-reported Dominic Interactive for Adolescents (DIA) for 444 children. Associations were estimated using negative binomial models for each PFAS. Bayesian kernel machine regression (BKMR) models were performed to assess the exposure mixture effect on children's behavior.In our study population, 73% of mothers had spent more than 12 y in education. Higher scores on SDQ externalizing subscale were observed with increasing cord-serum concentration of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) [adjusted mean ratio (aMR)=1.18, 95% confidence interval (CI): 1.03, 1.34, and aMR=1.14 (95% CI: 1.00, 1.29) for every doubling of concentration, respectively]. Results for the hyperactivity score were similar [aMR=1.20 (95% CI: 1.04, 1.40) and aMR=1.18 (95% CI: 1.02, 1.36), respectively]. With regard to major depressive disorder and internalizing subscales, perfluorodecanoic acid (PFDA) was associated with higher self-reported DIA scores [aMR=1.14 (95% CI: 1.01, 1.27) and aMR=1.11 (95% CI: 1.02, 1.21), respectively]. In terms of the anxiety subscale, PFDA and PFNA were associated with higher scores [aMR=1.11 (95% CI: 1.02, 1.21) and aMR=1.10 (95% CI: 1.01, 1.19), respectively]. Concurrent increases in the PFAS concentrations included in the BKMR models showed no change in the SDQ externalizing and DIA internalizing subscales scores.Prenatal exposure to PFNA and PFOA were associated with increasing scores for measures of externalizing behaviors, specifically hyperactivity. We also identified associations between PFNA and PFDA prenatal exposure levels and increasing scores related to internalizing behaviors (general anxiety and major depressive disorder), which adds to the as yet sparse literature examining the links between prenatal exposure to PFAS and internalizing disorders. https://doi.org/10.1289/EHP12540.
Efficient SARS-CoV-2 infection antagonization by rhACE2 ectodomain multimerized onto the Avidin-Nucleic-Acid-NanoASsembly
Authors: Simone Bernardotto, Ilaria Frasson, Silvia Faravelli, Annalisa Morelli, Elisa Schiavon, Giulia Yuri Moscatiello, Martina Bruna Violatto, Alberta Pinnola, Anselmo Canciani, Andrea Mattarei, Gianpaolo Rossi, Marisa Brini, Laura Pasetto, Valentina Bonetto, Paolo Bigini, Federico Forneris, Sara N. Richter, Margherita Morpurgo
Journal: Biomaterials (2023)

Nanodecoy systems based on analogues of viral cellular receptors assembled onto fluid lipid-based membranes of nano/extravescicles are potential new tools to complement classic therapeutic or preventive antiviral approaches. The need for lipid-based membranes for transmembrane receptor anchorage may pose technical challenges along industrial translation, calling for alternative geometries for receptor multimerization. Here we developed a semisynthetic self-assembling SARS-CoV-2 nanodecoy by multimerizing the biotin labelled virus cell receptor -ACE2-ectodomain onto a poly-avidin nanoparticle (NP) based on the Avidin-Nucleic-Acid-NanoASsembly-ANANAS. The ability of the assembly to prevent SARS-CoV-2 infection in human lung cells and the affinity of the ACE2:viral receptor-binding domain (RBD) interaction were measured at different ACE2:NP ratios. At ACE2:NP = 30, 90 % SARS-CoV-2 infection inhibition at ACE2 nanomolar concentration was registered on both Wuhan and Omicron variants, with ten-fold higher potency than the monomeric protein. Lower and higher ACE2 densities were less efficient suggesting that functional recognition between multi-ligand NPs and multi-receptor virus surfaces requires optimal geometrical relationships. In vivo studies in mice showed that the biodistribution and safety profiles of the nanodecoy are potentially suitable for preventing viral infection upon nasal instillation. Viral receptor multimerization using ANANAS is a convenient process which, in principle, could be rapidly adapted to counteract also other viral infections.
Internal-state-dependent control of feeding behavior via hippocampal ghrelin signaling
Authors: Ryan W.S. Wee, Karyna Mishchanchuk, Rawan AlSubaie, Timothy W. Church, Matthew G. Gold, Andrew F. MacAskill
Journal: Neuron (2023)

Hunger is an internal state that not only invigorates feeding but also acts as a contextual cue for higher-order control of anticipatory feeding-related behavior. The ventral hippocampus is crucial for differentiating optimal behavior across contexts, but how internal contexts such as hunger influence hippocampal circuitry is unknown. In this study, we investigated the role of the ventral hippocampus during feeding behavior across different states of hunger in mice. We found that activity of a unique subpopulation of neurons that project to the nucleus accumbens (vS-NAc neurons) increased when animals investigated food, and this activity inhibited the transition to begin eating. Increases in the level of the peripheral hunger hormone ghrelin reduced vS-NAc activity during this anticipatory phase of feeding via ghrelin-receptor-dependent increases in postsynaptic inhibition and promoted the initiation of eating. Together, these experiments define a ghrelin-sensitive hippocampal circuit that informs the decision to eat based on internal state.
How is preterm birth working out: cardiopulmonary response to exercise in extreme prematurity
Authors: Erik B. Hysinger, Paul Critser
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Adult survivors of extreme preterm birth have impaired exercise tolerance with reduced oxygen consumption that appears to be related to decreased muscular fitness or alterations in oxygen delivery to the skeletal muscle.</b>https://bit.ly/3tOBF84
AAV vectors displaying bispecific DARPins enable dual-control targeted gene delivery
Authors: Samuel A. Theuerkauf, Elena Herrera-Carrillo, Fabian John, Luca J. Zinser, Mariano A. Molina, Vanessa Riechert, Frederic B. Thalheimer, Kathleen Börner, Dirk Grimm, Petr Chlanda, Ben Berkhout, Christian J. Buchholz
Journal: Biomaterials (2023)

Precise delivery of genes to therapy-relevant cells is crucial for in vivo gene therapy. Receptor-targeting as prime strategy for this purpose is limited to cell types defined by a single cell-surface marker. Many target cells are characterized by combinations of more than one marker, such as the HIV reservoir cells. Here, we explored the tropism of adeno-associated viral vectors (AAV2) displaying designed ankyrin repeat proteins (DARPins) mono- and bispecific for CD4 and CD32a. Cryo-electron tomography revealed an unaltered capsid structure in the presence of DARPins. Surprisingly, bispecific AAVs transduced CD4/CD32a double-positive cells at much higher efficiencies than single-positive cells, even if present in low amounts in cell mixtures or human blood. This preference was confirmed when vector particles were systemically administered into mice. Cell trafficking studies revealed an increased cell entry rate for bispecific over monospecific AAVs. When equipped with an HIV genome-targeting CRISPR/Cas cassette, the vectors prevented HIV replication in T cell cultures. The data provide proof-of-concept for high-precision gene delivery through tandem-binding regions on AAV. Reminiscent of biological products following Boolean logic AND gating, the data suggest a new option for receptor-targeted vectors to improve the specificity and safety of in vivo gene therapy.
Apixaban versus no anticoagulation for the prevention of venous thromboembolism in children with newly diagnosed acute lymphoblastic leukaemia or lymphoma (PREVAPIX-ALL): a phase 3, open-label, randomised, controlled trial
Authors: Sarah H O'Brien, Vilmarie Rodriguez, Glen Lew, Jane W Newburger, Corinna L Schultz, Etan Orgel, Kimberly Derr, Mark A Ranalli, Adam J Esbenshade, Jessica Hochberg, Hyoung Jin Kang, Yulia Dinikina, Donna Mills, Mark Donovan, Joshua L Dyme, Nicholas A Favatella, Lesley G Mitchell
Journal: The Lancet Haematology (2023)